Is the log partition low on space? If the log partition free space drops below 4GB, no mail will flow. That's happened to me a few times, lol. ;) Usually because I was moving mailboxes and it loaded up the logs. Restart the Exchange System Attendant and see if a few emails go out. Check the queues to see if they're loaded. If disk space isn't the issue, reboot the server.

i'm wondering though that turning off cache mode for these particular users may not be a good idea.

they are email hogs, with around 10 gig of email each.

For remote users I suggest downloading the Office GPO templates. From there you can control that while in cached mode it only downloads the header information until the email is clicked on to open or in preview mode. This can save a ton of bandwidth. Remember, cached mode is so you can view your email in offline mode, there is no reason while in the office to have cached mode turned on since you are always connected.

It was a yes or no question, lol. I take back what I said about "no mail will flow"...if disk space is low (7 times out of 10 the crux of mailflow issues), wavering around the cutoff point...some messages will trickle through, and it will be slow, but the system will appear to be up. Behavior for internal and remote users is *not* the same for numerous reasons. The queues will keep trying to clear themselves and squeak a few through, according to priority, but back pressure has already built. Internal messages will get priority to that limited resource. It's a valid thing to check and only takes a minute. If it's not the case, move on to the next suggestion.

At this point, it's perception it's only the remote users...a symptom possibly of a system-wide issue. Internal users will think everything is working because they can send internally to each other (that always drops last). They might not even know, yet, mail isn't going outbound (just because it left the local network client's Outlook Outbox, doesn't mean it isn't sitting in an Exchange queue). They may be shortly following remote users with calls to the help desk. SO, as a good fellow offering free advice from 15 years of managing Exchange...I suggest a common solution-checklist to mailflow issues (things sitting in multiple outboxes going nowhere), to perhaps prevent a larger interruption of workflow ;) Check server disk space, system resources, and queues, restart services, and reboot the box. If it were one remote user having the issue, I'd delete the OST and let it rebuild. Multiple users at the same time, it's an Exchange server or connectivity issue.

If it persists after reboot: are queues still jammed up? How are the remote users connecting? VPN, RPC, WAN...can they send that same file using OWA? How are send/receive connectors and queues configured? Are remote users' mailboxes on a different database? Is there any filtering software or appliance or 3rd party service in play? Do you have more than one Exchange server...are remote Outlook profiles connecting to the right server? Did anybody change anything on the server today, roll out any client patches, firewall changes, change tick boxes for authentication in Exchange Server IIS? Are there authentication or DNS errors in your DC event logs, etc. See...now it gets into consulting hours, lol, hence the obvious checks, first.